CN106146326A - A kind of acetyl-salicylic derivate crystal and its production and use - Google Patents
A kind of acetyl-salicylic derivate crystal and its production and use Download PDFInfo
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- CN106146326A CN106146326A CN201510151946.2A CN201510151946A CN106146326A CN 106146326 A CN106146326 A CN 106146326A CN 201510151946 A CN201510151946 A CN 201510151946A CN 106146326 A CN106146326 A CN 106146326A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C219/00—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C219/02—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C219/04—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C219/14—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having at least one of the hydroxy groups esterified by a carboxylic acid having the esterifying carboxyl group bound to a carbon atom of a six-membered aromatic ring
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/60—Salicylic acid; Derivatives thereof
- A61K31/618—Salicylic acid; Derivatives thereof having the carboxyl group in position 1 esterified, e.g. salsalate
- A61K31/621—Salicylic acid; Derivatives thereof having the carboxyl group in position 1 esterified, e.g. salsalate having the hydroxy group in position 2 esterified, e.g. benorylate
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/06—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton from hydroxy amines by reactions involving the etherification or esterification of hydroxy groups
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- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
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Abstract
The invention discloses a kind of acetyl-salicylic derivate 2-(lignocaine) ethyl Aspirin ester hydrochloride crystal and its production and use.A characteristic peak is had at following 2 θ angles: 11.0 ° ± 0.2 ° on X-ray powder diffraction (XRPD) figure of described crystal, 20.6 ° ± 0.2 °, 25.1 ° ± 0.2 °, 8.2 ° ± 0.2 °, 16.5 ° ± 0.2 °, 13.4 ° ± 0.2 °, 25.4 ° ± 0.2 °.
Description
Technical field
The present invention relates to chemical pharmacy field, particularly relate to a kind of acetyl-salicylic derivate 2-(lignocaine)
Ethyl Aspirin ester hydrochloride crystal and its production and use.
Background technology
Aspirin, has another name called aspirin, is synthesized first in 1853, and is employed in 1899
In clinical treatment.Aspirin has multi-medicament effect, and it plays alleviation head in a short time by vasodilation
The effect of pain, therefore can be used to Antipyretic.Aspirin is the choice drug for the treatment of rheumatic fever, after medication
Can antipyretic, reduce inflammation, make joint symptoms take a turn for the better, erythrocyte sedimentation rate decline.In addition to rheumatic arthritis, these product are also
For treating rheumatoid arthritis, symptom can be improved, create conditions for treatment further.Additionally, Ah Si
Woods is for osteoarthritis, ankylosing spondylitis, juvenile arthritis and the skeleton of other non-rheumatic inflammations
Myalgia is sick, also can relief of symptoms.Aspirin on platelet populated with inhibitory action, thus blood can be stoped
Bolt is formed, and can be clinically used for preventing temporal cerebral ischemia seizure, myocardial infarction, atrial fibrillation, artificial heart
Valve or other postoperative thrombosis are it can also be used to treat unstable angina pectoris.Aspirin also may be used
It is used for alleviating mucocutaneous lymph node syndrome (mucocutaneous lymphnode syndrome).Research also finds, aspirin is in pre-anti-caking
The aspects such as intestinal cancer, rectal cancer, esophageal carcinoma serve effect.Therefore, aspirin purposes in treatment is
The most valuable.
But, oral aspirin is easily generated gastrointestinal untoward reaction.Topmost have dyspepsia, stomach
With symptoms such as duodenal hemorrhage, gastric ulcer and gastritis.Therefore, research worker is attempting studying other always
The aspirin derivatives of route of administration, in the hope of being alleviated or avoided gastrointestinal tract produced by Aspirin not
Good reaction.
Chinese patent CN 101484415B discloses a kind of water-soluble prodrugs of aspirin (a kind of acetyl water
Poplar acid derivative), in treatment, this prodrug can enter internal by transdermal administration, it is to avoid common Ah Si
The gastrointestinal side effect that Linkou County's clothes produce.
But, above-mentioned patent does not disclose any compound crystal form of water-soluble prodrugs of aspirin.Research solid
Drug crystal forms is conducive to the stability controlling medicine in preparation, storage process.Feature according to crystal formation determines preparation
Technique, improves the performance of solid pharmaceutical preparation, can effectively ensure that production batch between pharmacokinetics.Therefore, it is thus achieved that
The crystal formation of compound is to ensure that the important measures of drug quality.
Summary of the invention
The present invention provides a kind of acetyl-salicylic derivate 2-(lignocaine) ethyl 2-acetoxyl group first
Benzoate hydrochlorate crystal.
It is a further object to provide described 2-(lignocaine) ethyl Aspirin ester salt
The preparation method of hydrochlorate crystal.
It is also another object of the present invention to provide described 2-(lignocaine) ethyl Aspirin ester salt
The purposes of hydrochlorate crystal.
Fourth object of the present invention is to provide a kind of containing 2-(lignocaine) ethyl Aspirin
The pharmaceutical composition of ester hydrochloride crystal.
In a first aspect of the present invention, it is provided that a kind of 2-(lignocaine) ethyl Aspirin ester hydrochloride
Salt crystal, its chemical constitution shown in formula I, on X-ray powder diffraction (XRPD) figure of described crystal under
State 2 θ angles and have a characteristic peak: 11.0 ° ± 0.2 °, 20.6 ° ± 0.2 °, 25.1 ° ± 0.2 °, 8.2 ° ± 0.2 °, 16.5 ° ± 0.2 °,
13.4 ° ± 0.2 °, 25.4 ° ± 0.2 °；
In another preference, on X-ray powder diffraction (XRPD) figure of described crystal at following 2 θ angles also
There is a characteristic peak: 10.8 ° ± 0.2 °.
In another preference, on X-ray powder diffraction (XRPD) figure of described crystal at following 2 θ angles also
There is a characteristic peak: 22.8 ° ± 0.2 °, 30.4 ° ± 0.2 °, 19.2 ° ± 0.2 °, 17.6 ° ± 0.2 °, 10.6 ° ± 0.2 °, 23.0 ° ± 0.2 °,
35.7 ° ± 0.2 °, 27.9 ° ± 0.2 °, 18.2 ° ± 0.2 °, 24.8 ° ± 0.2 °, 22.1 ° ± 0.2 °.
In another preference, the infrared absorption spectroscopy of described crystal is at 2988.0cm-1, 2974.6cm-1,
2953.7cm-1, 2889.1cm-1, 1725.9cm-1, 1759.1cm-1, 1605.6cm-1, 1576.1cm-1,
1484.0cm-1, 1448.2cm-1, 1389.9cm-1, 1068.7cm-1, 1087.1cm-1, 757.0cm-1,
And scope 2487.3cm-1-2563.4cm-1There is absworption peak at place；More preferably, described crystal has as shown in Figure 1
Infrared spectrum.
In a second aspect of the present invention, it is provided that a kind of 2-(lignocaine) ethyl Aspirin ester
Hydrochlorate crystal, shown in formula I, described crystal is rhombic form to its chemical constitution, uses X-ray monocrystalline
Diffraction, lattice parameter is: α=β=γ=90 °；
In another preference, using X-ray single crystal diffraction to measure, described crystal also includes the feature that
-crystallographic space groups: Pbca；
-elementary cell volume:
-crystal size: 0.211 × 0.176 × 0.112mm3；
-crystalline density: 1.267mg/m3；
Asymmetry unit number in-lattice: 8；
Number of electrons in-unit cell: F (0000)=1344.
In a third aspect of the present invention, it is provided that 2-(lignocaine) ethyl that a kind of present invention as above provides
The preparation method of Aspirin ester hydrochloride crystal, described method includes step:
(1) by 2-(lignocaine) ethyl Aspirin ester hydrochloride crude material and anhydrous acetonitrile
Mixing, makes raw material be completely dissolved, obtains solution；
(2) solution is cooled to 0-30 DEG C, separates out 2-(lignocaine) ethyl that the present invention as above provides
Aspirin ester hydrochloride crystal.
In another preference, described 2-(lignocaine) ethyl Aspirin ester hydrochloride crude product
Raw material is 1:2-1:20w/v with the final mass volume ratio of anhydrous acetonitrile；More preferably, for 1:4-1:10w/v.
In another preference, described course of dissolution needs heating；More preferably, described course of dissolution needs to add
Heat refluxes to making anhydrous acetonitrile.
In another preference, carry out the crystal that (2nd) step separates out filtering, being dried；Described filtration side
Method uses sucking filtration；Described dry employing is vacuum dried, and more preferably uses vacuum to be spin-dried for.
In another preference, solution is cooled to 4-25 DEG C and separates out crystal.
In a fourth aspect of the present invention, it is provided that 2-(lignocaine) ethyl that a kind of present invention as above provides
The purposes of Aspirin ester hydrochloride crystal, for preparing the medicine for the treatment of aspirin indication.
In another preference, described aspirin indication is selected from: cold, fever, headache, neuralgia,
Myalgia, dysmenorrhea, rheumatic fever, rheumatic arthritis, gout, cancer, diabetes, diabetic complication,
Cardiovascular and cerebrovascular disease, prevention of stroke, prevention ischemic heart desease, prevention transient ischemic attack, prevention cardiac muscle thromboembolism,
Reduce ARR M & M.
In another preference, the dosage form of described medicine is oral administered dosage form or transdermal administration；More preferably
Ground, selected from oral liquid, capsule, tablet, solution, emulsion, ointment, latex, gel preparations.
In a fifth aspect of the present invention, it is provided that a kind of pharmaceutical composition, containing controlling in described pharmaceutical composition
Treat 2-(lignocaine) the ethyl Aspirin ester hydrochloride that the present invention as above of effective dose provides
Salt crystal and pharmaceutically acceptable carrier；
In another preference, the dosage form of described pharmaceutical composition is oral administered dosage form or transdermal administration；
More preferably, the dosage form of described pharmaceutical composition selected from oral liquid, capsule, tablet, solution, emulsion, ointment,
Latex, gel preparations.
In a sixth aspect of the present invention, it is provided that the preparation method of a kind of pharmaceutical composition, described method bag
Include step: by 2-(lignocaine) the ethyl 2-acetyl oxygen of the present invention as above offer of therapeutically effective amount
Yl benzoic acid ester hydrochloride crystal and the mixing of pharmaceutically acceptable carrier, obtain pharmaceutical composition.
Accordingly, the invention provides a kind of 2-(lignocaine) ethyl Aspirin ester hydrochloride
New crystal.
Accompanying drawing explanation
Fig. 1 shows that 2-of the present invention (lignocaine) ethyl Aspirin ester hydrochloride is brilliant
The infrared absorpting light spectra of body.
Fig. 2 shows that 2-of the present invention (lignocaine) ethyl Aspirin ester hydrochloride is brilliant
The X-ray single crystal diffraction structure chart of body.
Detailed description of the invention
The qualification of 2-(lignocaine) ethyl Aspirin ester hydrochloride crystal and character
2-(lignocaine) the ethyl Aspirin ester hydrochloride crystal that the present invention provides uses multiple
Its character is studied by mode and instrument.
" X-ray powder diffraction (XRPD) " is the common test being currently used for measuring crystal structure (i.e. crystal formation)
Method.Use x-ray powder diffraction instrument, produce a series of diffracting spectrum when X-ray transparent crystal, should
Diffracted rays different in collection of illustrative plates and intensity thereof are determined by the atomic group of a fixed structure, thereby determine that the tool of crystal
Body crystalline structure.
The method of the X-ray powder diffraction measuring crystal is well known in the art.The 2-(two of the present invention
Ethylamino) ethyl Aspirin ester hydrochloride crystal has specific crystal habit, in X-ray
Powder diffraction (XRPD) figure has specific characteristic peak.Specifically, the 2-(lignocaine) of the present invention
Following on X-ray powder diffraction (XRPD) figure of ethyl Aspirin ester hydrochloride crystal
There is a characteristic peak at 2 θ angles: 11.0 ° ± 0.2 °, 20.6 ° ± 0.2 °, 25.1 ° ± 0.2 °, 8.2 ° ± 0.2 °,
16.5 ° ± 0.2 °, 13.4 ° ± 0.2 °, 25.4 ° ± 0.2 °；In a preferred embodiment, this figure
Compose and also have characteristic peak at following 2 θ angles: 10.8 ° ± 0.2 °；In one more preferably embodiment, this figure
Compose and also have characteristic peak at following 2 θ angles: 22.8 ° ± 0.2 °, 30.4 ° ± 0.2 °, 19.2 ° ± 0.2 °,
17.6 ° ± 0.2 °, 10.6 ° ± 0.2 °, 23.0 ° ± 0.2 °, 35.7 ° ± 0.2 °, 27.9 ° ± 0.2 °, 18.2
° ± 0.2 °, 24.8 ° ± 0.2 °, 22.1 ° ± 0.2 °；More preferably, described 2-(lignocaine) ethyl 2-
The X-ray powder diffraction result detailed data of acetoxy-benzoic acid ester hydrochloride crystal is as shown in table 1, institute
The measurement parameter used includes:
Measuring condition: Cu-K α；
Pipe pressure/pipe flow: 40kV/40mA；
Scanning angle: 3.0221 °-44.9861 °
Table 1
2-(lignocaine) the ethyl Aspirin ester hydrochloride crystal of the present invention may be used without infrared
Atlas Method (IR) detects, and its assay method is well known in the art.The infared spectrum of this crystal shows
At 2988.0cm-1, 2974.6cm-1, 2953.7cm-1, 2889.1cm-1, 1725.9cm-1, 1759.1cm-1,
1605.6cm-1, 1576.1cm-1, 1484.0cm-1, 1448.2cm-1, 1389.9cm-1, 1068.7cm-1,
1087.1cm-1, 757.0cm-1, and scope 2487.3cm-1-2563.4cm-1There is absworption peak at place.Preferably have
There is the infared spectrum basically identical with Fig. 1.
" X-ray single crystal diffraction " is to utilize monocrystal to the diffraction effect of X-ray to measure crystal structure
Experimental technique.2-(lignocaine) the ethyl Aspirin ester hydrochloride crystal that the present invention provides
Using X-ray single crystal diffraction to measure, its principal character includes:
-rhombic form；
-lattice parameter:
α=β=γ=90 °.
In a preferred embodiment, 2-(lignocaine) the ethyl 2-that X-ray single crystal diffraction measures is used
Acetoxy-benzoic acid ester hydrochloride crystal, its principal character also includes:
-crystallographic space groups: Pbca；
-elementary cell volume:
-crystal size: 0.211 × 0.176 × 0.112mm3；
-crystalline density: 1.267mg/m3；
-asymmetry unit number in lattice: 8；
-the number of electrons in unit cell: F (0000)=1344.
In another preferred embodiment, described 2-(lignocaine) ethyl Aspirin ester hydrochloride
The X-ray single crystal diffraction structure chart of salt crystal is substantially consistent with shown in Fig. 2.
In an embodiment more preferably, the angle of the data collection that described X-ray single crystal diffraction sets
Degree scope is at 1.895 °-25.997 °.
2-(lignocaine) the ethyl Aspirin ester hydrochloride crystal that the present invention provides has purity
High (99.3%), the advantage such as good stability.
2-(lignocaine) ethyl Aspirin ester hydrochloride crystal preparation method
In order to obtain the crystalline substance of 2-of the present invention (lignocaine) ethyl Aspirin ester hydrochloride
Body, inventor is through repeatedly attempting, and crystallization effect is the most undesirable, and concrete outcome is as follows:
A () takes 10g 2-(lignocaine) ethyl Aspirin ester hydrochloride crude material, add
20-30ml dichloromethane is allowed under perfect solution, stirring condition be slowly added to n-hexane or petroleum ether solution,
There is white solid slowly to separate out, but crystalline solid form is bad.
B () takes 10g 2-(lignocaine) ethyl Aspirin ester hydrochloride crude material, add
5mL-15mL dichloromethane, is heated to reflux 1 hour making raw material be completely dissolved, after being slowly cooled to room temperature,
Not separating out solid, place more than 24 hours, separate out a small amount of solid under-20 DEG C of freezing conditions, crystalline solid form is not
Good.
C () takes 10g 2-(lignocaine) ethyl Aspirin ester hydrochloride crude material, add
25ml ethanol dissolve, be heated to 50 DEG C, make raw material slowly dissolve, be cooled to room temperature, solid do not separate out or
Separate out a small amount of.
Inventor, through constantly selection and optimization, finally determines one and prepares 2-(lignocaine) ethyl 2-
The method of acetoxy-benzoic acid ester hydrochloride crystal, its crystallization effect is good and efficiency high, and described method includes
Following steps:
The first step, by 2-(lignocaine) ethyl Aspirin ester hydrochloride crude material and anhydrous second
Nitrile mixes, and makes raw material be completely dissolved, obtains solution；
Second step, makes precipitation white crystal by solution cooling.
In the above-mentioned first step, 2-(lignocaine) ethyl Aspirin ester hydrochloride crude material and nothing
After water-acetonitrile mixing, it is heated to reflux temperature, makes 2-(lignocaine) ethyl Aspirin ester hydrochloride
Crude material is completely dissolved；2-(lignocaine) ethyl Aspirin ester hydrochloride crude material and addition
The final mass volume range of anhydrous acetonitrile at 1:2-1:20w/v；Preferably at 1:4-1:10w/v.
In one embodiment, it is in a heated condition, is continuously added to anhydrous acetonitrile and 2-(lignocaine) ethyl
Aspirin ester hydrochloride crude material, stirring mixing, until 2-(lignocaine) ethyl 2-acetyl oxygen
Yl benzoic acid ester hydrochloride crude material is completely dissolved, and obtains solution.
In above-mentioned second step, solution is cooled to 0-30 DEG C；It is preferably cooled to 4-25 DEG C.
In one more preferably embodiment, carry out the white crystal obtained in second step filtering, being dried.Institute
State filter method and use sucking filtration；Described dry employing is vacuum dried, and more preferably uses vacuum to be spin-dried for.
2-(lignocaine) the ethyl Aspirin related in the above-mentioned preparation method that the present invention provides
Ester hydrochloride crude material can be obtained by the method that this area is conventional, and the parameter related in these methods is originally
Skilled person can be determined by limited number of time experiment.The described method obtaining raw material include but not
It is limited to,
(1) with aspirin as raw material, react with thionyl chloride under catalyst action and obtain adjacent acetyl water
Poplar acyl chlorides, reacts generation 2-(lignocaine)-ethyl Aspirin ester afterwards with diethylaminoethanol,
Last react with hydrogen chloride gas that to obtain 2-(lignocaine) ethyl Aspirin ester hydrochloride crude product former
Material.Course of reaction is as shown in formula III.Wherein, described with thionyl chloride reactions steps in, described catalyst
It is selected from, but not limited to: DMF, pyridine, DIPEA, more preferably reacts temperature
Degree scope is at 40 DEG C-60 DEG C, and preferred aspirin is 1:1.1 with the equivalent proportion of thionyl chloride.Institute
State with in diethylaminoethanol reactions steps, preferred diethylaminoethanol and the reaction of acetyl salicylic acyl chlorides
Equivalent proportion is 1:1, and preferred range of reaction temperature is at 10 DEG C-30 DEG C, and the preferred response time is at 2-6
Hour, preferred after having reacted with diethylaminoethanol, use methyl tertiary butyl ether(MTBE) molten as extraction
Agent, regulation pH value of solution to alkalescence (being preferably adjusted to pH7.1-10.0, more preferably to pH8.0-9.0), ice bath extracts
Take.Described with hydrogen chloride gas reactions steps, preferred needs control to be passed through the amount of hydrogen chloride gas, make
Reactant liquor pH scope is at pH3.0-4.0.
(2) with aspirin as raw material, under dehydrant effect, 2-(diethylamino is generated with diethylaminoethanol dehydration
Base)-ethyl Aspirin ester, reacts with hydrogen chloride gas subsequently and obtains 2-(lignocaine) ethyl 2-acetyl
P-methoxybenzoic acid ester hydrochloride crude material.Course of reaction is as shown in formula IV.Wherein, at aspirin and diethylamino
In base ethanol synthesis step, described dehydrant is selected from, but not limited to: N, N-dicyclohexylcarbodiimide (DCC),
N, N '-DIC (DIC), DMAP (DMAP).Wherein, reacted by adjustment
The conditions such as temperature, response time and catalyst, can improve the yield of end product.Reaction temperature needed for each step,
Response time, the need of and the how condition such as selecting catalyst, those skilled in the art can be by the reality of limited number of time
Test and be determined.
(3) with aspirin as raw material, under catalyst action, 2-(diethylamino is reacted into lignocaine bromoethane
Base)-ethyl Aspirin ester, reacts with hydrogen chloride gas subsequently and obtains 2-(lignocaine) ethyl 2-acetyl
P-methoxybenzoic acid ester hydrochloride crude material.Course of reaction is as shown in formula V.Wherein, in described aspirin and second
In amino bromoethane reactions steps, the catalyst of use is selected from, but not limited to: cesium carbonate, potassium carbonate, sodium carbonate,
Triethylamine, pyridine.Wherein, by adjusting the conditions such as reaction temperature, response time and catalyst, can improve final
The yield of product.Reaction temperature needed for each step, the response time, the need of and the how bar such as selecting catalyst
Part, those skilled in the art can be determined by the experiment of limited number of time.
The purposes of 2-(lignocaine) ethyl Aspirin ester hydrochloride crystal and combinations thereof thing
According to Chinese patent CN 101484415B disclosure, the 2-(lignocaine) obtained by the present invention
Ethyl Aspirin ester hydrochloride can be used for treating any by the way of oral or transdermal administration
The indication of aspirin (aspirin), the preferably mode of transdermal administration, it is possible to reduce common Ah Si
The side effect of woods intestines and stomach.2-(lignocaine) ethyl Aspirin ester obtained by the present invention
Hydrochlorate crystal is prone to storage and uses, and purity high (99.3%), therefore can provide as crude drug or
For preparing prevention or treating the medicine of the disease that various aspirin can effectively play a role.Wherein, institute
State the disease that aspirin can effectively play a role to be selected from: cold, fever, headache, neuralgia, myalgia,
Dysmenorrhea, rheumatic fever, rheumatic arthritis, gout, cancer, diabetes, diabetic complication, heart and brain
Angiopathy, prevention of stroke, prevention ischemic heart desease, prevention transient ischemic attack, prevention cardiac muscle thromboembolism,
Reduce ARR M & M.
Therefore, the invention still further relates to comprise 2-of the present invention (lignocaine) ethyl Aspirin ester salt
The pharmaceutical composition of hydrochlorate crystal, described pharmaceutical composition contains the 2-of therapeutically effective amount (lignocaine) second
Base Aspirin ester hydrochloride crystal, and pharmaceutically acceptable carrier.
As used herein, term " contain " or " including " include " comprising ", " substantially by ...
Constitute " and " by ... constitute ".Term " therapeutically effective amount " refers to people and/or animal to be produced merit
Can or activity and the amount that can be accepted by people and/or animal.
As used herein, term " pharmaceutically acceptable " refers to be applicable to people and/or animal and nothing is excessive the most not
Good side reaction (such as toxicity, stimulation and allergy), i.e. has the material of rational benefit/risk ratio.Term
" pharmaceutically acceptable carrier " refers to the carrier for Therapeutic Administration, including various excipient and diluent.
This term refers to so some medicament carriers: themselves be not necessary active component, and does not has after using
Undue toxicity.Suitably carrier is well known to those of ordinary skill in the art.In " Lei Mingdun medicine section
Learn " (Remington ' s Pharmaceutical Sciences, Mack Pub.Co., N.J.1991) can find
About discussing fully of pharmaceutically acceptable excipient.
Preferably, described " pharmaceutically acceptable carrier " is selected from: filler, disintegrating agent, lubricant,
Fluidizer, effervescent, correctives, covering material, excipient or slow/controlled releasing agent.In the composition, medicine
On, acceptable carrier can contain liquid, such as water, saline, glycerol and ethanol.It addition, in these carriers
There is likely to be complementary material, such as filler, disintegrating agent, lubricant, fluidizer, effervescent, profit
Humectant or emulsifying agent, correctives, pH buffer substance etc..Generally, these materials can be formulated in nontoxic,
In inert and pharmaceutically acceptable aqueous carrier medium.
Additionally, medicine composition dosage form preferred oral dosage form of the present invention and transdermal administration, such as
Oral liquid, capsule, tablet, solution, emulsion, ointment, latex, gel preparations etc..
The features described above that the present invention mentions, or the feature that embodiment is mentioned can be in any combination.This case description
Disclosed all features can be with any composition forms use, and each feature disclosed in description can
Replace with any alternative characteristics providing identical, impartial or similar purpose.Therefore except there being special instruction,
Disclosed feature is only the impartial or general example of similar features.
Main advantages of the present invention are:
1, a kind of stable 2-(lignocaine) ethyl Aspirin ester hydrochloride is obtained first brilliant
Body, is to ensure that this compound prepares important measures quality controllable during medicine.
What 2, the present invention provided prepares 2-(lignocaine) ethyl Aspirin ester hydrochloride crystal
Method, energy consumption is low, stable yield, it is easy to industrialized production.
Below in conjunction with specific embodiment, the present invention is expanded on further.Should be understood that these embodiments are only used for
The bright present invention rather than restriction the scope of the present invention.The experiment side of unreceipted actual conditions in the following example
Method, generally according to normal condition or according to the condition proposed by manufacturer.Unless otherwise indicated, otherwise institute
Some percent, ratio, ratio or number are by weight.
The unit in percent weight in volume in the present invention is well-known to those skilled in the art, e.g.
Refer to the weight of solute in the solution of 100 milliliters.
Unless otherwise defined, all specialties used in literary composition are ripe with one skilled in the art institute with scientific words
The same meaning known.Additionally, any method similar or impartial to described content and material all can be applicable to
In the inventive method.Preferable implementation described in literary composition only presents a demonstration with material and is used.
Embodiment 1
The preparation of 2-(lignocaine) ethyl Aspirin ester hydrochloride crystal
A. 2-(lignocaine) ethyl Aspirin ester hydrochloride crude material is prepared
With toluene as solvent, DMF is catalyst, under the conditions of reaction temperature 50 DEG C, makes
Aspirin reacts with equivalent proportion 1:1.1 with thionyl chloride, reacts 2 hours, and reaction generates adjacent acetyl
Bigcatkin willow acyl chlorides；Then, diethylaminoethanol and acylate neighbour's acetyl salicylic acyl chlorides are carried out with equivalent proportion 1:1
Reaction, reaction temperature is 25 DEG C, and the time is 4 hours, and reaction generates 2-(lignocaine)-ethyl 2-acetyl oxygen
Yl benzoic acid ester；Methyl tertiary butyl ether(MTBE) aqueous phase extracted, phase ice bath alkali tune of fetching water；Re-using isopropyl acetate is
Extractant, aqueous phase extracted, take isopropyl acetate phase；With isopropyl acetate as solvent in salification process, subsequently
The strict amount controlling to be passed through hydrogen chloride gas, making reactant liquor pH is about 3.5.Reaction end obtains 2-(diethyl
Amino) ethyl Aspirin ester hydrochloride crude material.
B. 2-(lignocaine) ethyl Aspirin ester hydrochloride crystal is prepared
Under heated reflux condition, to 2-(lignocaine) ethyl Aspirin ester hydrochloride crude product
Raw material is continuously added to anhydrous acetonitrile stirring mixing, until 2-(lignocaine) ethyl Aspirin
Ester hydrochloride is completely dissolved.Wherein, 2-(lignocaine) ethyl Aspirin ester hydrochloride crude product
Raw material is 1:4 with the final mass volume ratio of anhydrous acetonitrile.Slowly cool to 25 DEG C, separate out white crystal,
Carry out solid vacuum after sucking filtration to be spin-dried for.
Embodiment 2
The X-ray powder diffraction of 2-(lignocaine) ethyl Aspirin ester hydrochloride crystal measures
The crystal of 2-(lignocaine) the ethyl Aspirin ester hydrochloride obtained by Example 1
Carrying out X-ray powder diffraction, the detecting instrument of use is: Panalytical X ' Pert Powder powder X-ray
X ray diffractometer x；Measuring condition: Cu-K α；Pipe pressure/pipe flow: 40kV/40mA；Scanning angle: 3.0221
°-44.9861°；Scanning step: 0.0260 °；Transmitting slit: 0.2177；Test temperature: 25 DEG C.?
The data arrived are as shown in table 1.
Table 1
Embodiment 3
The X-ray single crystal diffraction of 2-(lignocaine) ethyl Aspirin ester hydrochloride crystal measures
2-(lignocaine) ethyl Aspirin ester hydrochloride crystal obtained by Example 1 enters
Row X-ray single crystal diffraction, using instrument is Bruker SMART APEX CCD single crystal diffractometer；Test
Temperature: 293K；Scanning wavelength:Absorb correction factor: 0.243mm-1；Data collection
Angular range: 1.895 °-25.997 °；Diffraction index scope :-17≤h≤19 ,-8≤k≤8,
-24≤l≤35.Fig. 2 is shown in by structure chart.The characteristic obtained is characterized as below:
-rhombic form；
-lattice parameter:α=β=γ=90 °.
-crystallographic space groups: Pbca；
-elementary cell volume:
-crystal size: 0.211 × 0.176 × 0.112mm3；
-crystalline density: 1.267mg/m3；
-asymmetry unit number in lattice: 8；
-the number of electrons in unit cell: F (0000)=1344.
Embodiment 4
The preparation of 2-(lignocaine) ethyl Aspirin ester hydrochloride crystal
A. 2-(lignocaine) ethyl Aspirin ester hydrochloride crude material is prepared
With aspirin as raw material, with chloroform as solvent, N, N-dicyclohexylcarbodiimide is dehydrant
(aspirin and N, the equivalent proportion of N-dicyclohexylcarbodiimide is 1:2), with diethylaminoethanol with
The reaction of equivalent proportion 1:1.2 generates 2-(lignocaine)-ethyl Aspirin ester, is subsequently passed chlorination
Hydrogen, reacted and in the strict amount controlling to be passed through hydrogen chloride gas so that pH is at about pH3.0.Reaction
Obtain 2-(lignocaine) ethyl Aspirin ester hydrochloride crude material.
B. 2-(lignocaine) ethyl Aspirin ester hydrochloride crystal is prepared
In a heated condition, to 2-(lignocaine) ethyl Aspirin ester hydrochloride crude material
In be continuously added to anhydrous acetonitrile stirring mixing, until 2-(lignocaine) ethyl Aspirin
Ester hydrochloride is completely dissolved, wherein, and 2-(lignocaine) ethyl Aspirin ester hydrochloride crude product
Raw material is 1:10 with the final mass volume ratio of anhydrous acetonitrile.Slowly cool to 4 DEG C, separate out white crystal,
Carry out solid vacuum after sucking filtration to be spin-dried for.
Embodiment 5
The infrared absorption spectrometry of 2-(lignocaine) ethyl Aspirin ester hydrochloride crystal
2-(lignocaine) ethyl Aspirin ester hydrochloride crystal obtained by Example 4 enters
Row infrared absorption spectrometry, using instrument is Nicolet iZ10 Fourier transformation infrared spectrometer.Use
Pellet technique；Number of sample scan: 32；Number of background scan: 32；Resolution: 4.000；Sampling
Gain: 1.0；Index glass speed: 0.6329.The infrared absorption spectroscopy obtained is as shown in Figure 1.
Embodiment 6
The stability test of 2-(lignocaine) ethyl Aspirin ester hydrochloride crystal
2-(lignocaine) ethyl Aspirin ester hydrochloride crystal obtained by Example 1,
Under the conditions of being placed in 25 DEG C ± 2 DEG C, respectively at 0 month, 3 months, 6 months, 9 months, sampling in 12 months,
Detect pH value, have related substance and content.Wherein, pH value is to take sample about 1.0g, and add water 50mL, shakes
Shake 10 minutes, filter, take subsequent filtrate 10mL pH meter and detect；Related substance and content is had all to use efficiently
Liquid Detection (external standard method).Result shows, crystal of the present invention places 12 under the conditions of 25 DEG C ± 2 DEG C
Individual month, its stability was the best.Concrete data are shown in Table 2.
Table 2
The foregoing is only presently preferred embodiments of the present invention, be not limited to the substantial technological of the present invention
Context, the substantial technological content of the present invention is broadly to be defined in the right of application, appoints
What other people technology entities that completes or method, if with the right of application defined in phase completely
With, also or the change of a kind of equivalence, all it is covered by being considered among this right.
Claims (10)
1. 2-(lignocaine) ethyl Aspirin ester hydrochloride crystal, its chemical constitution such as Formulas I
Shown in, X-ray powder diffraction (XRPD) figure of described crystal has characteristic peak at following 2 θ angles: 11.0 ° ± 0.2 °,
20.6 ° ± 0.2 °, 25.1 ° ± 0.2 °, 8.2 ° ± 0.2 °, 16.5 ° ± 0.2 °, 13.4 ° ± 0.2 °, 25.4 ° ± 0.2 °；
2. crystal as claimed in claim 1, it is characterised in that the X-ray powder diffraction of described crystal
(XRPD) also has characteristic peak on figure at following 2 θ angles: 10.8 ° ± 0.2 °.
3. crystal as claimed in claim 1 or 2, it is characterised in that the X-ray powder diffraction of described crystal
(XRPD) also have characteristic peak on figure at following 2 θ angles: 22.8 ° ± 0.2 °, 30.4 ° ± 0.2 °, 19.2 ° ± 0.2 °,
17.6 ° ± 0.2 °, 10.6 ° ± 0.2 °, 23.0 ° ± 0.2 °, 35.7 ° ± 0.2 °, 27.9 ° ± 0.2 °, 18.2 ° ± 0.2 °, 24.8 ° ± 0.2 °,
22.1°±0.2°。
4. crystal as claimed in claim 1, it is characterised in that the infrared absorption spectroscopy of described crystal exists
2988.0cm-1, 2974.6cm-1, 2953.7cm-1, 2889.1cm-1, 1725.9cm-1, 1759.1cm-1,
1605.6cm-1, 1576.1cm-1, 1484.0cm-1, 1448.2cm-1, 1389.9cm-1, 1068.7cm-1,
1087.1cm-1, 757.0cm-1, and scope 2487.3cm-1-2563.4cm-1There is absworption peak at place.
5. 2-(lignocaine) ethyl Aspirin ester hydrochloride crystal, its chemical constitution is such as
Shown in Formulas I, described crystal is rhombic form, uses X-ray single crystal diffraction to measure, and lattice parameter is:α=β=γ=90 °；
6. crystal as claimed in claim 5, it is characterised in that use X-ray single crystal diffraction to measure, institute
State crystal also to include the feature that
-crystallographic space groups: Pbca；
-elementary cell volume:
-crystal size: 0.211 × 0.176 × 0.112mm3；
-crystalline density: 1.267mg/m3；
Asymmetry unit number in-lattice: 8；
Number of electrons in-unit cell: F (0000)=1344.
7. 2-(lignocaine) the ethyl Aspirin ester salt as described in claim 1-6 is arbitrary
The preparation method of hydrochlorate crystal, it is characterised in that described method includes step:
(1) by 2-(lignocaine) ethyl Aspirin ester hydrochloride crude material and anhydrous acetonitrile
Mixing, makes raw material be completely dissolved, obtains solution；
(2) solution is cooled to 0-30 DEG C, separates out 2-(lignocaine) second as described in claim 1-6 is arbitrary
Base Aspirin ester hydrochloride crystal.
8. preparation method as claimed in claim 7, it is characterised in that described 2-(lignocaine) ethyl 2-
Acetoxy-benzoic acid ester hydrochloride crude material is 1:2-1 with the final mass volume ratio of anhydrous acetonitrile:
20w/v；It is preferably 1:4-1:10w/v.
9. preparation method as claimed in claim 7, it is characterised in that solution is cooled to 4-25 DEG C of precipitation
Crystal.
10. 2-(lignocaine) the ethyl Aspirin ester salt as described in claim 1-6 is arbitrary
The purposes of hydrochlorate crystal, it is characterised in that for preparing the medicine for the treatment of aspirin indication.
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| CN202211136957.XA CN115521216A (en) | 2015-04-01 | 2015-04-01 | Acetylsalicylic acid derivative crystal, and preparation method and application thereof |
| CN201510151946.2A CN106146326B (en) | 2015-04-01 | 2015-04-01 | Acetylsalicylic acid derivative crystal and preparation method and application thereof |
| US15/562,222 US10532973B2 (en) | 2015-04-01 | 2016-03-07 | Acetylsalicylic acid derivative crystal, its preparation method and use |
| PCT/CN2016/075753 WO2016155468A1 (en) | 2015-04-01 | 2016-03-07 | Acetylsalicylic acid derivative crystal and preparation method and use thereof |
| EP16771223.1A EP3279182B1 (en) | 2015-04-01 | 2016-03-07 | Acetylsalicylic acid derivative crystal and preparation method and use thereof |
| JP2017567519A JP6496429B2 (en) | 2015-04-01 | 2016-03-07 | Crystals of acetylsalicylic acid derivative and preparation method and use thereof |
| US16/676,575 US10882817B2 (en) | 2015-04-01 | 2019-11-07 | Acetylsalicylic acid derivative crystal, its preparation method and use |
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| CN111565708A (en) * | 2017-10-26 | 2020-08-21 | 浙江越甲药业有限公司 | Stable pharmaceutical composition containing non-steroidal anti-inflammatory drug derivatives |
| CN115448905A (en) * | 2022-09-28 | 2022-12-09 | 浙江越甲药业有限公司 | Benzoic acid ester derivatives |
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| US3365483A (en) * | 1963-06-05 | 1968-01-23 | Starogardzkie Zakl Farma | Process for obtaining diethylaminoethanol acetylsalicylate hydrochloride |
| CN105143174A (en) * | 2013-03-15 | 2015-12-09 | 苏州泰飞尔医药有限公司 | Novel high penetration drugs and their compositions thereof for treatment of parkinson diseases |
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| WO2008007171A1 (en) | 2006-07-09 | 2008-01-17 | Techfields Biochem Co. Ltd | Positively charged water-soluble prodrugs of aspirin |
| CN104276962B (en) * | 2013-07-08 | 2019-04-12 | 浙江越甲药业有限公司 | A kind of aspirin derivatives and combinations thereof and application |
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| US3365483A (en) * | 1963-06-05 | 1968-01-23 | Starogardzkie Zakl Farma | Process for obtaining diethylaminoethanol acetylsalicylate hydrochloride |
| CN105143174A (en) * | 2013-03-15 | 2015-12-09 | 苏州泰飞尔医药有限公司 | Novel high penetration drugs and their compositions thereof for treatment of parkinson diseases |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111565708A (en) * | 2017-10-26 | 2020-08-21 | 浙江越甲药业有限公司 | Stable pharmaceutical composition containing non-steroidal anti-inflammatory drug derivatives |
| CN111565708B (en) * | 2017-10-26 | 2023-07-25 | 浙江越甲药业有限公司 | Stable pharmaceutical composition containing non-steroidal anti-inflammatory drug derivative |
| US11986453B2 (en) | 2017-10-26 | 2024-05-21 | Zhejiang Yuejia Pharmaceuticals Co., Ltd | Stable pharmaceutical composition containing non-steroidal anti-inflammatory drug derivative |
| CN115448905A (en) * | 2022-09-28 | 2022-12-09 | 浙江越甲药业有限公司 | Benzoic acid ester derivatives |
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| EP3279182A4 (en) | 2018-12-12 |
| EP3279182A1 (en) | 2018-02-07 |
| WO2016155468A1 (en) | 2016-10-06 |
| US20200123098A1 (en) | 2020-04-23 |
| CN115521216A (en) | 2022-12-27 |
| EP3279182B1 (en) | 2021-05-26 |
| US20180305296A1 (en) | 2018-10-25 |
| JP2018508581A (en) | 2018-03-29 |
| CN106146326B (en) | 2022-10-11 |
| JP6496429B2 (en) | 2019-04-03 |
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| US10882817B2 (en) | 2021-01-05 |
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